How do faults in the WFS1 gene lead to cell death in Wolfram syndrome?

Research details

Type of funding: PhD Studentship

Grant Holder: Dr Patrick Yu-Wai-Man

Institute: Newcastle University

Region: North East

Start date: October 2015

End Date: September 2018

Priority: Causes

Eye Category: Neuro-ophthalmology

Overview

In Wolfram syndrome the cells that carry visual signals from the eye to the brain (known as retinal ganglion cells) die off over time. People with Wolfram syndrome start to lose their sight as young children and are usually registered blind by mid- late adulthood. At the moment there is no treatment but we do know that the syndrome is linked to faults in the gene WFS1.

Previous research suggests that WSF1 is involved with the way that cells produce the energy they need to survive and work. In this project the student is studying some of the processes that can lead to cell death, such as poor energy production, to find out exactly how WSF1 is involved. The team will use what they learn to develop a zebrafish model of Wolfram as a future drug screeing tool.

Investigating disease mechanisms in Wolfram syndrome secondary to WFS1 mutations and development of a zebrafish model

Wolfram syndrome is a neurodegenerative disorder caused by pathogenic autosomal recessive mutations within the WFS1 gene. The phenotype is characterised by variable combinations of endocrinological and neurological features, but a defining pathological feature of Wolfram syndrome is the marked tissue-specific loss of retinal ganglion cells (RGCs) with subsequent optic nerve degeneration. The onset of visual loss occurs in early childhood and it is relentlessly progressive with the majority of patients being registered legally blind by mid- to late adulthood. There is currently no effective treatment and the management of patients with visual loss remains largely supportive.

WFS1 encodes for a transmembrane protein (wolframin) that localises to the endoplasmic reticulum (ER). There is mounting evidence that the ER has a close dynamic relationship with the mitochondrial compartment and these activities are focused at physical areas of contact known as mitochondria-associated membranes (MAMs).

The research team is using a collection of five fibroblast cell lines harbouring confirmed pathogenic WFS1 mutations to systematically investigate a number of interrelated pathological mechanisms that ultimately precipitate apoptosis, namely, ER stress, disturbed calcium homeostasis and compromised mitochondrial energy production. To complement these in vitro experiments, they are further characterising an in vivo zebrafish model of Wolfram syndrome by knocking down WFS1 expression in zebrafish embryos with specifically targeted morpholino oligonucleotides.

The overriding synergistic aims of this research project are to clarify the fundamental pathological mechanisms that contribute to RGC loss and to provide us with a versatile disease model to screen promising neuroprotective compounds that could prevent further visual deterioration in patients with Wolfram syndrome.